Abstract
Abstract Background Microbiotica is developing MB310, a live biotherapeutic product consisting of 8 bacterial strains for the treatment of ulcerative colitis (UC). These were selected based on association with clinical responses in UC patients in a fecal microbiota transplantation (FMT) clinical study. To understand how MB310 drives clinical benefit, we tested their impact on epithelial barrier repair, innate immune cells, and CD4+ T lymphocytes, which are key to the pathology of UC. We also investigated the effects of MB310 bacterial metabolites on the induction of regulatory T (Treg) cells that can counteract UC-associated inflammation. Methods Effects on barrier function were assessed by measuring electric impedance of Caco-2 cells in the presence or absence of lipopolysaccharide (LPS). Effects on human dendritic cells (DCs) and M1 macrophages were assessed by determining their cytokine production profile. The effects of MB310 or its metabolites on CD4+ T cells were assessed by measuring their expression of the Treg markers Foxp3 and interleukin (IL)-10 following polarization with MB310-treated DCs. Finally, the induced Treg cells were functionally validated in a T cell suppression assay. Results Investigating barrier effects, we observed that five MB310 strains individually increased the integrity of a gut epithelial cell monolayer, and 2 strains repaired the monolayer following damage by LPS challenge. Furthermore, primary human monocyte-derived M1 macrophages and LPS-activated DCs showed an increase in the release of the anti-inflammatory cytokine, IL-10 in comparison to the pro-inflammatory cytokine tumor necrosis factor (TNF), following exposure to all MB310 strains. The MB310-treated DCs were able to enhance IL-10 production by T cells. Investigating the mechanisms of Treg induction, we revealed that the bacterial metabolites from two MB310 strains induced DCs to polarize two distinct subsets of actively suppressive Treg cells: Foxp3+ Tregs and IL-10-producing Tregs. Another MB310 species induced Foxp3+ suppressive Treg cells through direct effect on CD4+ T cells. Conclusion The accumulated data suggest that the strains of MB310 interact with the host to oppose key UC disease pathologies by improving gut epithelial barrier integrity; promoting an anti-inflammatory profile of innate immune cells; and inducing Treg cells. Moreover, the metabolites of some MB310 strains lead to induction of different types of functionally suppressive Treg cells. This highlights that multifaceted effects of MB310 that can circumvent the challenge of UC disease heterogeneity, proposing it as a potential therapeutic for a wide spectrum of UC patients. COMPOSER-1 is an ongoing phase 1b trial testing MB310 in UC patients.
Published Version
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